1. Field of the Invention
This invention relates to a method for treatment and prevention of inflammatory bowel disease which comprises administering an effective amount of a ribofuranose derivative or a pharmaceutically acceptable salt thereof to a mammal. This invention further relates to the use of such compounds in the preparation of a medicament for the treatment and prevention of inflammatory bowel disease.
2. Background of the Invention
Inflammatory bowel disease (IBD) is a term used in the art to generically encompass diseases of the intestine such as ulcerative colitis (UC), irritable bowel syndrome, irritable colon syndrome and Crohn's disease (CD). For many of these diseases, in particular CD, the origin of the disease (bacterial, viral or autoimmune) is unknown. There is sufficient overlap in the diagnostic criteria for UC and CD that it is sometimes impossible to say which a given patient has; however, the type of lesion typically seen is different, as is the localization. UC mostly appears in the colon, proximal to the rectum, and the characteristic lesion is a superficial ulcer of the mucosa; CD can appear anywhere in the bowel, with occasional involvement of stomach, esophagus and duodenum, and the lesions are usually described as extensive linear fissures. IBD is rather common, with a prevalence that is claimed to be in the range of 70-170 in a population of 100,000.
Crohn's disease is currently neither medically nor surgically curable, requiring approaches to treatment that maintains symptomatic control, quality of life, and minimizes short- and long-term toxicity of therapy. The current therapy of IBD usually involves the administration of anti-inflammatory or immunosuppressive agents, such as sulfasalazine, corticosteroids, 6-mercaptopurine/azathioprine, or cyclosporine, which usually bring only partial results. For example, IBD's such as Crohn's disease or ulcerative colitis have been treated in the past with salicylic acid derivatives (such as 5-aminosalicylic acid, also known as 5-ASA or mesalazine; and prodrugs thereof, such as sulfasalazine). Possible side effects of 5-ASA preparations include nausea, vomiting, heartburn, diarrhea and headaches. Other treatments have been based on corticosteroids such as cortisone, however prolonged use of steroids has been known to result in side effects such as weight gain, shrinking of the adrenal glands, gray cataract, glaucoma, osteoporosis and diabetes mellitus. The use of immune modifying drugs such as 6-mercaptopurine and its prodrug azathioprine against Crohn's disease has increased in recent years, but these drugs are slow acting and clinical activity cannot be expected until several weeks or even months of treatment has elapsed. In recent years the use of immunomodulating monoclonal antibodies that neutralize TNF-α has been contemplated, the only example of such an antibody that obtained marketing approval for use against Crohn's disease currently being infliximab. A drawback of this therapy is the high risk of severe infections when administered by injection and the risk of lymphoproliferative disease. A reported side effect of the treatment with infliximab is bilateral anterior toxic optic neuropathy.
If anti-inflammatory and/or immunosuppressive therapies fail, colectomies are the last line of defense. About 30% of CD patients will need surgery within the first year after diagnosis. In subsequent years, the rate is about 5% per year. Unfortunately, CD is characterized by a high rate of recurrence; about 5% of patients need a second surgery each year after initial surgery. In UC, a further reason for resorting to surgery is that the patients are known to be at much increased risk for developing colorectal cancer, starting 10-15 years after the diagnosis of ulcerative colitis. Presumably this is due to the recurrent cycles of injury to the epithelium, followed by regrowth, increasing the risk of transformation. Accordingly, colostomy is used as prophylaxis against the development of cancer in UC patients.
From the above it is evident that there still exists the need of drugs and therapies that are effective against inflammatory bowel diseases and that avoid the disadvantages of the prior art drugs and treatment.